1. Field of the Invention
The invention relates to an antiarrhythmic drug and particularly to a combination of d- and l-isomers of sotalol, being N-[4-[1-hydroxy-2-[(1-methylethyl)amino]ethyl] phenyl] methane sulfonamide, as a safer class III antiarrhythmic drug with reduced beta adrenergic blockade.
2. Description of the Related Art
Drug treatment of cardiac arrhythmias has undergone rapid changes during the last decade. Experimental studies have shown that drugs that act by delaying conduction, though are able to suppress ventricular arrhythmias, also increase the mortality particularly in patients with cardiac disease.
Cardiac Arrhythmia Suppression Trial (CAST) Investigators (New Engl J Med 1989; 321:407-412) and Cardiac Arrhythmia Suppression Trial II (CAST II) Investigators (New Engl J Med 1992; 327:227-33) have shown that drugs like flecainide, encainide and moricizine which act by blocking sodium channels cause increased mortality in patients who survived from acute myocardial infarction despite markedly suppressing premature ventricular contractions.
Coplen et al (Circulation 1990 Oct. 82(4):1106-16) have shown that even drugs like quinidine which has been used for so long in antiarrhythmic therapy increase the mortality in a variety of settings.
The Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation (CASCADE) study (Am J Cardiol 1993; 72:280-287) have further shown that, amiodarone, an antiarrhythmic agent which acts by increasing the duration of cardiac repolarization is better than those which act by blocking sodium channels.
The above disclosures emphasize the fact that suppression of arrhythmias does not necessarily decrease mortality and that the net effect on mortality is agent specific. In addition, the most important determinant of arrhythmia mortality is the nature and degree of ventricular dysfunction.
All these lead to dramatic changes in the choice of antiarrhythmic drugs for ventricular and supraventricular arrhythmias.
Thus, sotalol emerged as one of the drugs of choice for its beta blocking and antiarrhythmic activities, as it could reduce mortality by preventing ventricular fibrillation in patients with cardiac disease.
Jay W. Mason for the Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) Investigators (New Engl J Med 1993; 329:452-8) has shown that in patients with Ventricular Tachycardia (VT) and Ventricular Fibrillation (VF), sotalol a beta blocker with class III antiarrhythmic activity is better than six other class I antiarrhythmic compounds.
The results of the CAST and ESVEM trials have led to an increased interest in class III antiarrhythmic agents including sotalol (Callaghan et al, Am J. Cardiol, 1996; 78:(4A)(54-60).
Sotalol is being used as a equimolecular mixture of dextro- and laevo-isomer of the molecule. The isomers are equipotent in increasing the duration of repolarization and consequently the action potential duration and believed to be equally effective clinically as antiarrhythmic agent.
However, the laevo-isomer is a more potent beta blocker as compared to the dextro-isomer. As a result racemic sotalol with equal proportion of laevo- and dextro-isomers has more than required beta blocking activity which may compromise the cardiac function particularly in patients with structural heart disease.
In addition to the CAST trial a recent meta analysis of mortality data on 98000 survivors with myocardial infarction also found that class I agents were associated with increased mortality. Only class II and class III drugs were associated with decreased mortality. Unfortunately for a high percentage of these patients at risk, beta blockers are not tolerated or are contraindicated. The Survival With Oral d-Sotalol (SWORD) trial indicated that pure d-sotalol was also not of much benefit in patients with acute myocardial infraction (Am J. Cardiol 1995; 75:1023-1027).
U.S. Pat. No. 5,089,526 describes (+)-sotalol that is the dextro isomer as a class III antiarrhythmic drug capable of lengthening the action potential duration of cardiac cells and thus helpful in treatment of cardiac arrhythmias.
U K Patent 2,286,529 observes that the treatment of cardiac arrhythmias in patients with iscbaemic heart disease especially when accompanied by the signs and symptoms of heart failure presents a difficult problem, since most antiarrhythmic drugs including beta blockers, depress cardiac contractility and may worsen heart failure. In solving this problem this U K Patent finds that a mixture of the isomers of sotalol in which the proportion of l-isomer is significantly less than that of d-isomer will be of use in the treatment of arrhythmias in patients with ischaemic heart disease and/or heart failure. It further discloses a combination of 60 to 99 percentage of d-sotalol with 40 to 1 percentage of racemic or dl-sotalol which corresponds to 80 to 99.50 percentage of d-sotalol with 20 to 0.50 percentage of 1-sotalol as the most suitable range for this combination for treatment of heart patients.